Novel 19-nor-9-isosteroids



United States Patent Oflice 3,484,464 Patented Dec. 16, 1969 3,484,464 NOVEL 19-NOR-9-ISOSTEROIDS Eugene Farkas, Indianapolis, Ind., assi uor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Filed Aug. 13, 1965, Ser. No. 479,633 Int. Cl. C07c 171/06 U.S. C]. 260--397.4 3 Claims ABSTRACT OF THE DISCLOSURE Estranes and estrenes having a 9B (9-iso) configuration and exhibiting hormonal or anti-hormonal activity are described.

This invention relates to certain novel steroids having a hitherto unknown spatial configuration at the AB and BC ring fusions.

Steroids have been described in a generic sense as perhydrocyclopentanophenanthrenes. As a result of considering a steroid as a substituted perhydrophenanthrene, the nomenclature of the perhydrophenanthrene molecule has been adapted by steriod chemists in describing the spatial relationships at the AB and BC steroid ring fusions. In describing the configuration of the perhydrophenanthrenes, the standard terms, cis and trans, have been used to describe the relative orientation of the atoms or radicals of the AB and BC ring fusion, and the terms, syn and anti, have been used to describe the relative orientation of the atoms or radicals attached at the positions in the perhydrophenanthrene molecule corresponding to the 9 and 10 positions in a steroid. Thus, coprostane, a well-known steroid, is described as having a cis-anti-trans configuration and cholestane as having a trans-anti-trans configuration.

To further illustrate this point, the accompanying drawing shows a perhydrophenanthrene molecule. In the figure, the Xs indicate the four bridgehead atoms which, in this instance, are in the trans-anti-trans configuration.

There are sixteen possible arrangements for the atoms or radicals attached to these four bridgehead carbons, and these configurations are usually expressed as eight racemic pairs. These eight pairs are represented by the trans-anti-trans, cis-anti-trans, cis-syn-trans, cis-syn-cis, cis-anti-cis, trans-syntrans, trans-anti-cis and trans-syncis configurations. In a steroid having a A or A double bond, there is no atom or radical at the 5 position and thus there can be no cis or trans configuration for the AB ring fusion. Thus, considering only the configuration of the atoms or radicals attached at the 8, 9 and carbon atoms, it can be seen that there will be only half as many possible configurations for the radicals or atoms at 8, 9 and 10. Giving the hydrogen at the '8 position of the steroid a beta configuration, the four possible racemic configurations for the 8, 9 and 10 positions are the 8/3, 9a, 10,9 (the natural configuration), the 8,8, 93, 1011 (the well-known retro configuration), the 8,8, 90:, 10a (the 10- iso configuration described in my co-pending application, Ser. No. 389,484, filed Aug. 13, 1964) and the hitherto unknown 8/3, 9/5, 1013*(the 9-iso configuration).

The provision of all possible configurations for the A, B and C ring fusions, both when fully saturated and when a double bond is present at the 5 position, has been a challenge to steroid chemists for several years The syn thesis of these compounds has been made most difiicult by the fact that, in most naturally occurring steroids, there is a beta-oriented methyl group at the 10 position. The introduction of a methyl group at the 10 position or the reversal of the configuration of a bridgehead methyl group has been a synthetic problem which has defied solution until recently, except in one instance, this being the conversion of ergosterol into the retro configuration in lumisterol by the opening under the influence of ultraviolet light of the 9-10 bond and its: reclosing with a reversal of configuration. As a consequence of the difficulty of dealing with the IO-methyl compounds, most of the attempts to prepare steroids having substituents with unnatural configurations at the 5, 8, 9 and 10 carbon atoms has been carried out in the 19-nor series, which series has become readily avail-able by utilization of Birch reductions employing various readily available estratrienes as starting materials.

As indicated above, only one of the four possible racemates of known steroids having a double bond at the 5 position, the 8/3, 9,6, 10;? configuration, and only two of the possible saturated steroids, the trans-syn-cis and the cis-syn-cis configurations, have not hitherto been synthesized. It is an object of this invention to provide these hitherto unknown isomers. It is a further object of this invention to provide steroidal hormones having a novel spatial configuration plus an advantageous hormonal or anti-hormonal action. It is a still further object of this invention to provide novel intermediates for the synthesis of 19-nor retrosteroids, as well as other known steroids. Other objects of this invention will become apparent from the description which follows.

In fulfillment of the above and other objects, this invention provides compounds represented by the formulas wherein Z is a member of the group consisting of III clature having been proposed by Ieger et al., Helv. Chim. Acta., 2425 (1962). Illustrative lower aliphatic or halo-substituted lower aliphatic groups which R can represent in the above formulas contain from 1-3 carbon atoms and either may be saturated, or may contain an ethylenic linkage or an acetylenic linkage. Radicals illustrative of R thus include methyl, ethyl, isopropyl, vinyl, ethinyl, allyl, propargyl, chlorethinyl, bromethyl, chlorallyl, iodomethyl, fiuoromethyl and the like. In the above formulas, when either R or R" represents an acyloxy group, the acyl portion of the radical can contain either an aliphatic or an aromatic group, thus yielding acyloxy groups such as acetoxy, propionoxy, butyroxy, benzoxy, phenylacetoxy, naphthoxy, adamantanecar-boxy, cyclopentylpropionoxy and the like. In general, the acyloxy groups which R and R" can represent include all .the standard ester groupings, and these grouping can in turn contain substituents such as alkyl, nitro, chloro, alkoxy, etc.

In addition to the steroids specifically represented by the above formulas, this invention also includes substituted derivatives of those compounds, which derivatives are all well-known equivalents of the steroids specifically represented, including such obvious modifications as fiuoro, 6a-methyl, 16ot-hydroxy, Zoe-ChlOIO and the like, as well as compounds containing double bonds at positions in the steroid ring other than 4(5). In addition, this invention includes within its scope those compounds containing oxygen functions at C which series of compounds are generally known as the glucocorticoids and mineraloeorticoids.

The compounds of this invention which have a double bond at the 5 position are prepared by selectively hydrogenating the A900) double bond of a A4900) steroid in the presence of a supported noble metal catalyst at a hydrogen pressure of 3 atmo. or less and at a temperature below about 50 C. The noble metal catalyst which I prefer is palladium supported upon an alkaline earth salt, i.e., barium sulfate, barium carbonate, strontium carbonate, calcium sulfate and the like. To date, palladium supported on strontium carbonate seems to be the most effective catalyst in terms of relative yields of the 95,105 steroid. It will be noted that according to my co pending application, Ser. No. 389,484 filed Aug. 13, 1964, the ;,100: steroids are also prepared by hydrogenation of a A steroid over a noble metal catalyst. The catalysts disclosed therein are usually more active than a noble metal catalyst supported on an alkaline earth salt of the type utilized in this invention; that is to say, the more active noble metal catalysts are sufiiciently active to add alpha hydrogens to the 9,10 double bond regardless of the presence or absence of bulky substituents in the 17oz position. I have found out, however, that the A steroids which have an alpha substituent in the 17 position having a greater bulk than simply hydrogen permit the hydrogenation of the 9,10 double bond from the other side of the molecule and thus yield a 95,105 steroid rather than a 90t,100t steroid. Naturally, the bulkier the alpha-oriented group at C the higher the relative yield of 95,105 steroid. Apparently, the geometry of the molecule, particularly as regards the orientation of the substituents at C is of overriding importance with regard to the orientation of the hydrogens introduced into the molecule when comparatively inactive catalyst such as those illustrated above are employed to reduce the A steroid.

Since the process outlined above produces both the 95, isomers of this invention and the 9ot,10a isomers disclosed in my co-pending application, Ser. No. 389,484, filed Aug. 13, 1964, it is apparent that a chromatographic separation procedure will frequently be necessary to provide the 95,105 steroid free from the 9a,10a isomer although it is sometimes possible to crystallize directly the 95,105 compound from the hydrogenation mixture by seeding with previously Obtained crystals.

The compounds of this invention which have a hydrogen atom at the 5 position, rather than the terminus of a double bond, are prepared by reduction of a 9-iso-A steroid as furnished by the above procedure. If a beta configuration is desired for the hydrogen in the 5 position, reduction with a noble metal catalyst is the preferred procedure, whereas, if it is desired that the hydrogen in the 5 position have an alpha configuration, a Birch reduction or similar reduction procedure is employed to produce this configuration.

As mentioned above, the catalytic process of this invention can only be used to prepare compounds having a 17st substituent of greater bulk than a hydrogen atom. Compounds coming within the scope of the above formulas (I, II, and III) and having a hydrogen atom in the alpha position at C are prepared by synthetic procedures involving the use of a l9-nor-9-isosteroid having a substituent other than hydrogen as the starting material. For example, 9-isoestr 4 en--ol-3-one is prepared by oxidizing the corresponding 17a-hydroxy compound to a 3,17-diketone and then selectively reducing the 17 ketone to the corresponding 175-hydroxy compound by the use of a metal hydride. During this procedure, it is usually desirable to protect the ketone group at 3 prior to the initial oxidation step. If it is desired to prepare a 19-norpregnane with its acetyl side chain in the beta configuration, a suitable starting material is 17ot-ethinyl-55,95,105- estrane-175-ol-3-one. The acetylenic group of this compound can be hydrated to yield the corresponding 17aacetyl-175-ol derivative. Hydrogenolysis of this compound simultaneously removes the hydroxyl and epimerizes the acetyl group to yield the corresponding l75-acetyl derivative.

19-nor-9-isoprogesterone, another type of compound coming within the scope of Formula I above and having an alpha hydrogen at C can be prepared as follows: 9-isoestr-4-en-17a-ol-3-one is reduced to the corresponding 35,17a-diol. The hydroxyl at 3 is then selectively transformed to the 3-triphenylmethyl ether by reaction with triphenylmethyl chloride. Oxidation of the 17a-hydroxy to a ketone group followed by reaction of the ketone with sodium acetylide gives a 17a-ethinyl-175- hydroxy derivative. Hydration of this derivative to the l7a-acetyl compound followed by a hydrogenolysis procedure yields a compound having a beta-acetyl group and an alpha hydrogen at C Removal of the protective trityl group from the hydroxyl at C followed by oxidation with manganese dioxide yields the desired 19-nor-9- isoprogesterone.

Other synthetic methods for preparing compounds coming within the scope of the above formulas and having a hydrogen atom at the 17oz position will become readily apparent to those skilled in the art.

The A steroids which are the ultimate starting materials for the preparation of the compounds of this invention are furnished by the procedure set forth in US. Patent 3,086,027.

Not all of the compounds coming within the scope of the instant invention are preparable by the above procedures. For example, compounds containing an oxygen at C are not readily prepared from a A4900) compound because of the proximity of the 11 position to the 9(10) double bond. In this instance, the steroid lacking the 11 oxygen function is prepared by the above reduction procedure, and the oxygen function at C is then introduced by fermentation means employing such well-known oxygenating microorganisms as Rhizopus nigricans or Cunninghamella blakesleeanus. Other compounds containing groups which are removable by hydrogenation, such as halogen substituents, are prepared by introducing the halogen atom after the initial step of synthesizing the 19- nor-9-isosteroid.

The compounds of this invention have hormonal and antihormonal activity, the particular type of hormonal action depending upon the relationship of the particular compound to some naturally occurring hormone. For example, 17a-methyl-9-isoestr-4-en-17fi-ol-3-one is more than three times as potent an oral anabolic agent as is methyl testosterone, its stereoisomer. Similarly, 19-nor-9- iso-l7a-hydroxyprogesterone is a potent progestational agent, and 19-nor-9-iso DOPA has good mineralocorticoid action. Naturally, those compounds which have male hormone action are antagonistic to compounds having female hormone action as is well known in the art.

The compounds of this invention are also useful as intermediates. For example, treatment of a 19-nor-9isosteroid represented by Formula I above with acid yields the corresponding retro compound (9 3,100: configuration). Treatment of the same compound with base, on the other hand, yields a 3-keto-9p-estr5( 10)ene. Both of the above series of compounds have been synthesized recently, and the above procedures represent an improved process for their preparation.

Also included within the scope of this invention are the common derivatives of compounds represented by the above formulas such as ethers of the 17/3- or 17u-hydroxy compounds, acetonides of 16,17- or 17,21-dihydroxy compounds, esters of the 21-hydroxy compounds, tetrahydropyranyl ethers of the ZI-hydroxy compounds and so forth.

9-isosteroids coming within the scope of this invention include the following:

17a-vinyl-9-isoestr-4-en-l7,B-ol-3-one 17-benzoate, 17a-n-propyl-5a,9,8,10B-estran-l7B-ol-3-one, 17ot-isopropyl-5,8,9,,B,10B-estran-17fi-ol-3-one, 17u-chlorethinyl-9-isoestr-4-en-17fi-ol-3-one 17-acetate, 19-nor-9-isopregn-4-en- 1 75-01-3 ,20-dione, 19-nor-9-isopregn-4-ene-17B,2l-diol-3,20-dione 21- adamantoate, 19-nor-5ot,9fl-pregnane-17/3,2l-diol-3,20-dione 21- tetrahydropyranyl ether, 19-nor-5B,9fl-pregnane-l7fi,2l-diol-3,20-dione 21- cyclopentylpropionate, 19-nor-9-isopregn-4-ene-173,21-diol-3,20-dione 17,21-

acetonide, and 17ot-chlorovinyl-9-isoestr-4-en-17,8-ol-3-one.

This invention is further illustrated by the following specific examples:

EXAMPLE I 17a-methyl-9fl-estr-4-en-17fl-ol-3-one A suspension of 0.42 g. of palladium-on-barium sulfate in ml. of anhydrous ethanol was pro-reduced in a low pressure hydrogenation apparatus. One gram of 17amethylestra-4,9(10)-dien-17,B-ol-3-one in 20 ml. of anhydrous ethanol was then added, and the mixture was hydrogenated at a hydrogen pressure of about 3 atmo. until 1.1 equivalents of hydrogen had been absorbed. The time required for hydrogenation was about minutes. The mixture was removed from the hydrogenation appara tus, the catalyst was separated by filtration, and the filtrate evaporated to dryness in vacuo. An ultraviolet spectrum of the residue, which contained l7a-methyl-9fi-estr-4-en- 17,6-ol-3-one, had the following maxima:

A333,, e=5300; E83, e=1360 The residue was dissolved in 20 ml. of 3:2 benzenehexane solvent mixture and chromatographed over g. of Grade III neutral alumina. One-hundred sixteen eluate fractions of 50 ml. each were collected. The following table summarizes the results of this chromatographic separation procedure. In the table, column I gives the numbers of the eluate fractions and column II the solvent system employed for those fractions.

6 TABLE I Fraction number: Solvent system 1-83 3:2 benzene-hexane. 84-91 3:1 benzene-hexane. 92-104 Benzene. -110 9:1 benzene-ether. 111-115 Ether. 116 Methanol.

Fractions 31-71 were combined after evaporation of the solvents in vacuo. The combined weight of the resulting residue was 0.079 g., and the melting point of this crude material was 183-185 C. An ultraviolet spectrum of this residue had the following maxima:

A232, e=14,000; kit; 6 770 Recrystallization of the residue from other yielded crystalline material with about the same absorption at 243, but with virtually no absorption at 304, thereby showing an absence of any of the A starting material. An optical rotary dispersion curve on the recrystallized material was consistent with the expected 9-isoestrene structure.

Treatment of the crystalline material with one drop of 12N hydrochloric acid yielded the 95,100: (retro) com pound, as shown by an optical rotary dispersion curve.

EXAMPLE II 17 a-methyl-9 ,8-estr-4-en- -ol-3-one The above procedure was repeated except that palladium-on-strontium carbonate was employed as the catalyst. Twenty-one hundredths (0.21) gram of palladium-on-strontium carbonate in 15 ml. of anhydrous ethanol was pre-reduced. Five-tenths (0.5) gram of 17u-methyl-estra-4,9(10)-diene-17B-ol.-3-one in 20 ml. of ethanol were added. The mixture was hydrogenated at about 3 atmo. until 1.1 equivalents of hydrogen had been absorbed. This reduction required about 15 minutes. The catalyst was separated by filtration, and the residue crystallized from ether. Recrystallization of the residue yielded 0.079 g. of crystalline l7a-methyl-9fl-estr-4-en- 17,8-01-3-one melting in the range 155-170 C. and having the following ultraviolet maximum:

A233, 6 13,600 Recrystallization of these crystals from an ether-acetone mixture yielded purified 17a-rnethyl-9fl-estr-4-en-175-01- 3-one melting at about -196 C.;

REE e=16,850

A second fraction obtained from. the above filtrate proved to be chiefly the 90:,l0oc isomer melting at about 88-190" C.

EXAMPLE III Two drops of 12 N hydrochloric acid were added to a solution of 0.028 g. of 17a-methyl-9/i-estra-4-en-176-01- 3-one in 7 ml. of anhydrous methanol. The resulting solution was allowed to stand at room temperature for about two hours and was then poured into an excess of a saturated sodium chloride solution. The aqueous layer was extracted with an ether-methylene dichloride solvent mixture. The organic layer was separated, was washed with a saturated sodium chloride solution and was dried, and the solvents were removed by evaporation in vacuo. Recrystallization of the resulting residue from an etherhexane solvent mixture yielded crystals of 17a-methyl- 9p,10a-estr-4-en-17/8-ol-3-one, identical to an authentic sample of the retro compound according to vapor phase chromatography.

EXAMPLE IV 9 3-estr-4-en-17a-ol-3-one Following the procedure of Example I, a suspension of 0.096 g. of palladium-on-strontium carbonate in 15 ml.

of anhydrous ethanol was pre-reduced. A solution containing 0.23 g. of estra-4,9()-diene-17a-ol-3-one in ml. of anhydrous ethanol was added, and the resulting mixture was hydrogenated in a low pressure hydrogenation apparatus. About 1.1 equivalents of hydrogen were absorbed after about 19 minutes. The hydrogenation mixture was then removed from the apparatus, and the catalyst separated by filtration. Evaporation of the filtrate to dryness yielded 9-isoestr-4-en-17a-ol-3-one plus the corresponding 90:,10'04 isomer. Chromatography of the residue according to the procedure of Example I yielded the 9a,l0a isomer when a 4:1 benzene-hexane mixture was used as the eluant, and a mixture of the 9 3,105 and 9a,10a isomers when the solvent was changed to pure benzene. 9 8-estr-4-en-l7a-ol-3-one was separated from its 9a,10a isomer by recrystallization from an etheracetone solvent mixture.

Following the procedure of Example I, a suspension of 0.021 g. of palladium-on-barium sulfate in 20 ml. of anhydrous ethanol was pre-reduced. A solution of 0.05 g. of 17a-rnethyl-9-iso-estr-4-en-l7fi-ol-3-one in 20 ml. of ethanol was added, and the resulting mixture hydrogenated in a low pressure hydrogenation apparatus until about one equivalent of hydrogen had been absorbed. This reduction required about 26 minutes. The catalyst was separated by filtration, and the filtrate was evaporated to dryness in vacuo. Recrystallization of the resulting residue from ether yielded 0.27 g. of 17u-methyl-5/3,9fi, 10fl-estran-17fi-ol-3-one melting at about 116-118 C. Vapor phase chromatography of this compound showed it to be different from both the 5u,9a,10a and 5,8,9a,10u isomers. An optical rotary dispersion curve obtained from a sample of the above compound was completely consistent with the proposed 56,95,105 structure.

Analysis.Calc.: C, 78.57; H, 10.41. Found: C, 78.40; H, 10.51.

EXAMPLE VI 17a-methyl-5a,9fi,10/3-estran-17fi-ol-3-one One hundred milliliters of re-distilled liquid ammonia were placed in a three-neck round-bottom flask equipped with stirrer, condenser, and dropping funnel. Two-tenths gram of lithium in small pieces was slowly added to the liquid ammonia. The resulting solution of lithium in liquid ammonia was cooled in a Dry Ice bath while a solution of 0.1 g. of l7a-methyl-9fl-estr-4-en-l7fi-ol-3-one in 20 ml. of tetrahydrofuran was added. The reaction mixture was stirred for about 15 minutes, after which time an excess of an aqueous saturated ammonium chloride solution was added. The resulting mixture was allowed to warm up to room temperature over night, during which time the ammonia evaporated. The contents of the flask were partitioned between water and methylene dichloride. The organic layer was separated, was washed with saturated sodium chloride solution, and was dried, and the solvents removed therefrom by evaporation in vacuo. The resulting residue was dissolved in a 3:2 hexane-benzene solvent mixture and chromatographed over 15 g. of Grade III neutral alumina. One hundred 20-rnl. fractions were collected using the same solvent mixture as the eluant. Fractions 1049 yielded pure 17a-methyl- 504,95,l0fl-estran-l7 3-ol-3-one melting at about 177l78 C. after recrystallization from an hexane-ether solvent mixture. The optical rotary dispersion curve of this compound was consistent with the postulated 5a,9fi,l0fl structure.

Analysis.Calc.: C, 78.57; H, 10.41. Found: C, 78.29; H, 10.35.

I claim:

1. l7a-methyl-9B-estr-4-en-l7l3-ol-3-one.

2. 17tx-methyl-5a,9 3,10fl-estran-17f3-ol-3-one.

3. The process of preparing a 3-keto-A -l9-nor-9- isosteroid which comprises contacting a 3-keto-A -l9-nor- 9-isosteroid with aqueous base.

References Cited UNITED STATES PATENTS 3,207,753 9/1965 Bowers et al. 260--239.55 3,254,098 5/1966 Edwards 260--239.55

OTHER REFERENCES Steroids by Fieser et al., p. 595 relied on (1959).

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. l51; 260239.55, 397.3, 397.47, 397.5, 999

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,484,464 December 16, 1969 Eugene Farkas It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 8, lines 30 to 32, should appear as shown below:

3. The process of preparing a 3keto,5

[9isosteroid]9B,lOB steroid which comprises contacting a 3-keto-A"19nor[9isosteroid]9s, 10B steroid with aqueous base.

Signed and sealed this 5th day of January 1971.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

